The present invention was made with government support. Accordingly, the government has certain rights in the invention.
1. Field of the Invention
The present invention relates to recombinant DNA technology and to products and processes involved in the cloning preparation, expression, and use of genes for amyloid derived from the brain of Alzheimer's Disease patients.
2. Description of the Background Art
Senile plaques found in abundance in the Alzheimer's Disease (AD) brain represent a hallmark feature of this disorder and have been correlated with the degree of intellectual impairment (2, 3). The plaques are composed of extracellular amyloid, reactive cells, and degenerating neurites (1). The proteinaceous amyloid is also associated with the cerebral vasculature of the AD brain (6). Amyloid is composed of fibrils of 4-8 nm diameter that form the core of the plaques (4).
Protein chemistry studies have provided limited information on amyloid fibrillary material. Glenner and Wong (6) purified amyloid from meningeal vessels of an AD brain; a 4.2 kd polypeptide, known as .beta.-amyloid, was isolated and shown to have a unique amino acid sequence. A polypeptide of similar sequence was subsequently isolated from the cerebrovascular amyloid of a Down's syndrome brain (7); a single amino acid substitution, of glutamic acid for glutamine at position 11, distinguished the two polypeptides. Similar results were independently obtained, by Masters et al. (8) who partly purified and analyzed amyloid plaque cores from the AD cerebral cortex; the amino acid sequence of the Glu variant was obtained and is referred to as A4 amyloid.
The .beta.-polypeptide, derived from purified .beta.-amyloid, is disclosed in Glenner et al., U.S. Pat. No. 4,666,829, filed May 15, 1985. This patent also discloses antibodies made to the first 10 amino acids of the .beta.-polypeptide.
The amyloid gene product merits intense scrutiny since it is a major neuropathologic manifestation of AD. At present, no direct information is available on mechanisms that regulate amyloid metabolism and which are responsible for the increased deposition of amyloid in the AD brain. The gene has been localized to chromosome 21, as has the gene for familial AD (10, 11). Therefore, complex interactions involving chromosome 21 gene products (31), the processing of transcripts or of the protein precursor, an unusual precursor structure, and/or interaction with the environment may contribute to the unusually high content of amyloid in the AD brain (30).